ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.3262G>A (p.Ala1088Thr) (rs370078729)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766557 SCV000241953 uncertain significance not provided 2013-03-20 criteria provided, single submitter clinical testing This variant is denoted p.Ala1041Thr (GCT>ACT): c.3121 G>A in exon 5 of the PCDH19 gene (NM_001105243.1). The Ala1041Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is non-conservative as a non-polar amino acid residue is replaced by a polar Threonine residue. Ala1041Thr alters a position conserved in mammals in the cytoplasmic domain near the C-terminal region of the PCDH19 protein. However, multiple in-silico algorithms predict it may be benign. Therefore, based on the currently available information, it is unclear whether Ala1041Thr is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Athena Diagnostics Inc RCV000188341 SCV000614418 uncertain significance not specified 2017-04-27 criteria provided, single submitter clinical testing
Invitae RCV001065355 SCV001230311 uncertain significance Early infantile epileptic encephalopathy 9 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1088 of the PCDH19 protein (p.Ala1088Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs370078729, ExAC 0.008%). This variant has not been reported in the literature in individuals with PCDH19-related disease. ClinVar contains an entry for this variant (Variation ID: 206306). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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